Immune activation is a hallmark of human immunodeficiency virus-1 (HIV-1) infection and a significant factor that promotes continuous viral replication and CD4+ T-cell depletion. In HIV-infected individuals, levels of circulating activation markers correlate with accelerated disease progression and shortened survival. HIV infection is critically dependent on the activated state of CD4+ T cells since the virus cannot replicate efficiently in resting T cells. Quiescent T cells in blood are refractory to infection because of blocks at the level of reverse transcription and proviral integration. In addition, T-cell activation enhances viral transcription through the activation of various transcription factors, notably nuclear factor κB (NF-κB).
SIRT1 is a mammalian homologue of the yeast transcriptional repressor silent information regulator 2 (Sir2), an important factor governing longevity in yeast. Like Sir2, SIRT1 requires nicotinamide adenine dinucleotide (NAD+) as a cofactor, which links its activity to the metabolic state of the cell. In addition to its enzymatic activity on histone substrates in vitro, recent experimental evidence suggests that SIRT1 predominantly targets nonhistone proteins for deacetylation. It has been reported that Tat is a substrate for the deacetylase activity of SIRT1. Acetylation of lysine 50 (K50) in Tat is mediated by the histone acetyltransferase activities of p300 and human GCN5 and generates binding sites for the bromodomains of PCAF and Brg1. SIRT1 binds and deacetylates Tat at K50, a process necessary to recycle nonacetylated Tat protein for binding to TAR RNA and the cellular positive transcription elongation factor b (P-TEFb).
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